https://www.ajmc.com/newsroom/investigators-seek-to-better-understand-the-molecular-basis-of-polycythemia-vera
Investigators Seek to Better Understand the Molecular Basis of Polycythemia Vera

Kelly Davio

While a common genetic mutation among patients with polycythemia vera (PV) is V617F in exon 14 of the Janus kinase 2 (JAK2) gene—which activates the tyrosine kinase—it has been reported that patients with V617F-negative PV have mutations in exon 12 of JAK2. Exon 12 mutations are involved in approximately 3% of patients with PV, and these patients often have reduced erythroblasts in the bone marrow and hypercellular bone marrow.

A recent study from Pakistan sought to investigate the incidence of mutations of exon 12 and 14 in patients with PV and to correlate these mutations with patient characteristics and outcomes.

The investigators collected blood samples from 24 patients with PV, 16 of whom were men and 8 of whom were women. The patients’ blood was screened for mutations of exons 12 and 14 of JAK2. In total, 19 patients were positive for the hallmark gain of function mutation JAK2-V617F (which is estimated to be present in 97% of patients with PV), while 5 patients were negative.

Among the 5 patients who tested negative for the mutation, the investigators screened exon 14 to test for possible deletions or mutations. One patient was observed to have a V617A amino acid substitution instead of V617F. However, no deletions were observed. 

In exon 12, for which 10 nucleotide alterations have been previously described, the investigators found that a total of 3 mutated sites in exon 12 were found in 2 V617F-negative patients. However, many studies have concluded that mutations in exon 12 are often found in only a small proportion of granulocytes in some patients with PV, so given the low allelic burden and the heterogenic nature of the mutations, using exon 12 mutations to diagnose PV would likely be challenging.

The investigators did not find that clinical response of patients with mutant exon 12 was different from that of patients without these mutations, and hematological parameters of patients who had exon 12 mutations were not different from those of other patients with PV. Furthermore, there was no statistically significant difference in overall survival (OS) among groups; prior studies have shown that the 15-year OS among patients with the function mutation JAK2-V617F was 76%, while the 15-year OS among patients without the mutation was 94%.

The authors concluded that, while the gain of function mutation V617F is found in most patients with PV, among patients who do not have this hallmark mutation, analysis of exons 12 and 14 of JAK2 has revealed some underlying mutations that could potentially be used to diagnose PV on a genetic basis. In the future, write the authors, analysis of exon 12 nucleotide substitutions among a large group of patients will help to better understand their role in disease biology, progression, and outcomes.  

Reference
Akram AF, Kausar H, Chaudhary A, et al. Detection of exon 12 and 14 mutations in Janus kinase 2 gene including a noval mutant in V617F negative polycythemia vera patients from Pakistan. J Cancer. 2018;9(23):4341-4345. doi: 10.7150/jca.27414.
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